10-Propargyl-10-deazaminopterin (herein “PDX” or “10-propargyl-10dAM” or “pralatrexate”) is a member of a large class of compounds which have been tested and in some cases found useful in the treatment of tumors. This compound, which has the structure shown in FIG. 1, was disclosed by DeGraw et al., “Synthesis and Antitumor Activity of 10-Propargyl-10-deazaminopterin.” J. Medical Chem. 36: 2228-2231 (1993) and shown to act as an inhibitor of growth in the murine L1210 cell line and to a lesser extent of the enzyme dihydrofolate reductase (“DHFR”). In addition, some results were presented for the antitumor properties of the compound using the E0771 murine mammary tumor model. These data were equivocal because of the small number of mice used in the test (3 per dosage), the absence of any standard deviation information which would quantify the reliability of the data, and the fact that the highest dose used was in fact toxic to the mice. Nevertheless, assuming these data have some predictive value for the efficacy of a drug in treating human tumors, it would at best predict a drug which, at equivalent levels of tolerance, had properties comparable to or perhaps slightly better than methotrexate.
PCT Publication No. WO98/02163, discloses the surprising observation that more highly purified 10-propargyl-10-dAM compositions when tested in a xenograft model for their efficacy against human tumors have now been shown to be far superior to methotrexate (“MTX”) and are even superior to edatrexate (“ETX”), a more recent clinical candidate. Moreover, 10-propargyl-10dAM showed a surprising ability to cure tumors such that there was no evidence of tumor growth several weeks after the cessation of therapy. Thus, highly purified composition containing 10-propargyl-10dAM. can be used in accordance with the invention to treat tumors, including both solid tumors and leukemias. The composition is illustrated for use in treatment of human mammary tumors and human lung cancer.
Subsequent studies with 10-propargyl-10-dAM have shown that it is useful on its own and in combinations with other therapeutic agents. For example, Sirotnak et al., Clinical Cancer Research Vol. 6, 3705-3712 (2000) reports that co-administration of 10-propargyl-10-dAM and probenecid, an inhibitor of a cMOAT/MRP-like plasma membrane ATPase greatly enhances the efficacy of 10-propargyl-10-dAM against human solid tumors in vivo. 10-propargyl-10-dAM and combinations of 10-propargyl-10-dAM with platinum based chemotherapeutic agents have been shown to be effective against mesothelioma. (Khokar, et al., Clin. Cancer Res. 7: 3199-3205 (2001).
Another subsequent study showed that 10-propargyl-10-dAM has particular utility in the treatment of T-cell lymphomas, even with patients with drug resistant T-cell lymphomas, disclosed in U.S. Patent Publication No. 2005/0267117, which is incorporated by reference herein in its entirety. Other studies have shown a method for assessing sensitivity of a lymphoma to treatment with 10-propargyl-10-dAM by determining the amount of reduced folate carrier-1 enzyme (RFC-1) expressed by the sample, wherein a higher level of expressed RFC-1 is indicative of greater sensitivity to 10-propargyl-10-dAM, disclosed in PCT Publication No. WO 2005/117892, which is incorporated by reference herein in its entirety.
However, a need still remains in the art for determining which other cancers for which 10-propargyl-10-dAM has particular utility in treating, and also for methods for selecting patients for treatment with 10-propargyl-10-dAM, as well as methods for assessing sensitivity of a cancer including lymphoma to 10-propargyl-10-dAM. These and other needs are addressed by the present invention.
The term “lymphomas” refers to a variety of disease states, including Non-Hodgkins Lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL); follicular lymphoma (FL); Hodgkin's Disease; Burkitt's Lymphoma; cutaneous T-cell lymphoma; primary central nervous system lymphoma, and lymphomatous metastases. In most cases, lymphoma is characterized by the presence of cancerous B-cells. However, in T-cell lymphomas, the disease state is characterized by cancerous T-lymphocytes.
All references cited herein, both supra and infra, are hereby incorporated by reference herein in their entireties.